Small molecule inhibitors of USP1 deubiquitinating enzyme activity

Abstract

Provided are small molecule inhibitors of ubiquitin specific protease 1 (USP1) activity and methods for their use in treating and characterizing cancers. The small molecule USP1 inhibitors of the invention are particularly useful in the treatment of cancers that are resistant to DNA cross-linking agents.

What is claimed is: 
     
       1. A method for treating a subject having a breast cancer or an ovarian cancer, comprising:
 administering to a subject having breast cancer or ovarian cancer in need of such treatment a small molecule inhibitor of ubiquitin specific protease 1 (USP1) according to Formula I: 
 
       
         
           
           
               
               
           
         
         wherein
 X is O or S; 
 n is 0, 1, 2, 3, or 4; 
 each occurrence of R 1  is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR A ; —C(═O)R A ; —C(═O)N(R A ) 2 ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; —N(R A ) 2 ; —NHC(═O)R A ; —NR A C(═O)N(R A ) 2 ; —OC(═O)OR A ; —OC(═O)R A ; —OC(═O)N(R A ) 2 ; —NR A C(═O)OR A ; or —C(R A ) 3 ; wherein each occurrence of R A  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 R 2  is hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic, substituted or unsubstituted, heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR B ; —C(═O)R B ; —C(═O)N(R B ) 2 ; —SOR B ; —NHC(═O)R B ; —NR B C(═O)N(R B ) 2 ; or —C(R B ) 3 ; 
 wherein each occurrence of R B  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and 
 wherein when R 2  is substituted aliphatic, each substituent is independently selected from an aryl moiety, a heteroaryl moiety, an arylalkyl moiety, a heteroarylalkyl moiety, an alkoxy moiety, an aryloxy moiety, a heteroalkoxy moiety, a heteroaryloxy moiety, an alkylthio moiety, an arylthio moiety, a heteroalkylthio moiety, a heteroarylthio moiety, —F, —Cl, —Br, —I, —OH, —NO 2 , —CF 3 , —CH 2 CF 3 , —CHCl 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 NH 2 , —CH 2 SO 2 CH 3 , —C(O)R x , —CO 2 (R x ), —CON(R x ) 2 , —OC(O)R x , —OCO 2 R x , —OCON(R x ) 2 , —N(R x ) 2 , —S(O) 2 R x , —NR x (CO)R x , wherein each occurrence of R x  is independently an aliphatic moiety, a heteroaliphatic moiety, an aryl moiety, a heteroaryl moiety, an arylalkyl moiety, or a heteroalkyl moiety; 
 or a pharmaceutically acceptable salt thereof, 
 
         in an amount effective to treat the breast cancer or the ovarian cancer. 
       
     
     
       2. The method of  claim 1 , wherein the small molecule inhibitor of USP1 according to Formula I is the compound of Formula IV (527): 
       
         
           
           
               
               
           
         
       
     
     
       3. The method of  claim 1 , further comprising administering to the subject a DNA cross-linking agent. 
     
     
       4. The method of  claim 1 , further comprising administering to the subject a poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor. 
     
     
       5. The method of  claim 1 , further comprising administering to the subject a DNA cross-linking agent and a PARP inhibitor. 
     
     
       6. The method of  claim 1 , wherein X is O. 
     
     
       7. The method of  claim 1 , wherein n is 0. 
     
     
       8. The method of  claim 1 , wherein R 2  is substituted or unsubstituted phenyl. 
     
     
       9. The method of  claim 8 , wherein R 2  is phenyl substituted with halogen. 
     
     
       10. The method of  claim 1 , wherein the subject has breast cancer. 
     
     
       11. The method of  claim 1 , wherein the subject has ovarian cancer. 
     
     
       12. A method for treating a subject having a breast cancer or an ovarian cancer, comprising:
 administering to a subject having breast cancer or ovarian cancer in need of such treatment a small molecule inhibitor of ubiquitin specific protease 1 (USP1) according to Formula I: 
 
       
         
           
           
               
               
           
         
         wherein
 X is O; 
 n is 0, 1, 2, 3, or 4; 
 each occurrence of R 1  is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR A ; —C(═O)R A ; —C(═O)N(R A ) 2 ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; —N(R A ) 2 ; —NHC(═O)R A ; —NR A C(═O)N(R A ) 2 ; —OC(═O)OR A ; —OC(═O)R A ; —OC(═O)N(R A ) 2 ; —NR A C(═O)OR A ; or —C(R A ) 3 ; wherein each occurrence of R A  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 R 2  is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR B ; —C(═O)R B ; —C(═O)N(R B ) 2 ; —CO 2 R B ; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N 3 ; —N(R B ) 2 ; —NHC(═O)R B ; —NR B C(═O)N(R B ) 2 ; —OC(═O)OR B ; —OC(═O)R B ; —OC(═O)N(R B ) 2 ; —NR B C(═O)OR B ; or —C(R B ) 3 ; wherein each occurrence of R B  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 or a pharmaceutically acceptable salt thereof, 
 
         in an amount effective to treat the breast cancer or the ovarian cancer.